The American Diabetes Association estimates that Type II diabetes mellitus cost Americans $132 billion in 2002, making it and related metabolic syndrome the most widespread and costly metabolic diseases in our society. Furthermore, current estimates place the number of people with diabetes at 250 million worldwide by 2010, with 94% exhibiting Type II. These diseases are characterized by the inability to properly process circulating glucose. In early stage diabetes, patients exhibit hyperglycemia and hyperinsulinemia; disease progression can eventually lead to loss of both pancreatic beta cells and the ability to respond appropriately to circulating glucose. Current treatments can slow disease progression, but patients are still at high risk for vascular problems, poor wound healing, peripheral neuropathies, kidney and liver malfunctions, and a host of cellular- and immune-stress related problems. Two central issues are addressed in this proposal. First, not all diabetic patients develop the same sets of complications from hyperglycemia, indicating that the susceptibility to glucose toxicity has a genetic component. Second, current treatments are only partially effective in treating the disease, and new therapies -- including drug therapies -- will be required to improve prognosis. This Proposal presents a novel approach for identifying new genes and lead compounds to address these issues. By feeding a diet high in hexose sugars to the fruitfly Drosophila melanogaster, a number of defects were observed that are suggestive of metabolic problems in humans. Most notable is a robust developmental delay that has proven useful for screening purposes. Initial genetic screens have implicated pathways already linked to diabetes and glucose toxicity, including metabolic and stress pathways. Further, these 'high-glucose' flies respond to at least three different drugs that are commonly utilized in human diabetic patients, indicating that this model can also be useful for identifying lead therapeutic compounds. Flies will be screened with at least two hexose sugars to identify genetic loci that modify the developmental delay phenotype. Further, a novel approach will be utilized to screen flies in a high-throughput manner to identify new lead therapeutic compounds. Together, these genetic and compound screens should provide important functional information and the potential for new treatments.